Until recently, children with Hurler’s syndrome and other metabolic and immune deficiencies had a limited life span, while those with severe forms of such blood-related diseases as thalassemia and sickle cell anemia suffered from a variety of debilitating symptoms. The good news is that stem cell transplants are starting to change that picture. Many youngsters come to the Miller School of Medicine for treatment in which stem cells taken from their own, a matched sibling’s, or umbilical cord blood are reversing the effects of these tragic diseases. Kleiner and Paul Gordon, M.D., assistant professor of clinical pediatrics, hematology, and oncology, also are using stem cells to treat children with leukemia and with other cancers that have not responded to standard chemotherapy.

While the stem cell transplants given to Caleb and other children are an extraordinary advance in the treatment of these ailments, they represent just a tip of the iceberg of what scientists and physicians believe stem cells can offer. In laboratories across the University, researchers are beginning to tap the potential these cells hold for curing such conditions as diabetes, spinal cord injury, osteoarthritis, and rheumatoid arthritis.

Stem cells are immature cells that are able to replicate themselves and develop—or differentiate—into several cell types. Most cells of the body, such as brain or bone cells, are committed to serving a specific function. A stem cell remains uncommitted until it receives a signal to develop into a particular type of cell. Because of their flexibility and their ability to rapidly proliferate, researchers believe these cells hold tremendous potential for replacing damaged or diseased tissues and cells.

There are two types of stem cells—adult and embryonic. Adult stem cells exist in most tissues of the body and can become the specialized cell types of the tissue from which they originated. For example, when the blood-producing, or hematopoietic, stem cells in the blood are given to patients, they migrate to the patient’s bone marrow and produce platelets and red and white blood cells. Because adult stem cells form many, but not all, cell types, they are multipotent.

The more controversial stem cells, those derived from embryos that are a few days old, may develop into any type of cell in the body except those needed to develop a fetus. Unlike adult stem cells, once an embryonic stem cell is isolated, it is “immortal” and will continue to grow indefinitely. Embryonic stem cells are pluripotent because they can mature into any one of 200 cell types. Though adult stem cells are less versatile than embryonic stem cells, they offer great promise because replanting a patient’s own cells avoids the immune reactions seen with foreign tissue transplants.

The U.S. government limits its funding of stem cell research to only adult cells and to certain pre-existing human embryonic cell lines. Many of these, however, cannot be used for human therapy because they are contaminated with mouse “feeder” cells used in the culturing process, says Herman Cheung, the James L. Knight Professor of Biomedical Engineering. UM scientists are working with adult stem cells from humans and animals, and several have private funding that allows them to pursue embryonic stem cell studies.

At present, the only Miller School of Medicine facilities offering stem cell therapy are the pediatric immunology and hematology oncology divisions and the Bone Marrow Transplant Center. At this center, which opened 12 years ago, hundreds of adults have been treated with stem cells. Most patients here require high-dose chemotherapy, which significantly impairs their immune systems. To rebuild it, UM physicians harvest the patients stem cells from their own blood and return these to the bloodstream following treatment. If the patient is being treated for aplastic anemia or in certain cases of leukemia, stem cells are obtained from a donor or umbilical cord blood.

n the research front, some of the most promising work on stem cells is under way at The Miami Project to Cure Paralysis. Aiming to restore nerve function and ameliorate chronic pain experienced by people with spinal cord injuries, scientists there are looking at how stem cells transform into nerve cells under normal fetal development in animal models. Eventually, they hope to mimic this process to produce nerve cells in the laboratory, where they can be cultivated and used to treat patients with spinal cord injuries.

“We’re in the early stages of understanding the cell biology of human embryonic stem cells. Right now, we don’t have enough knowledge about how to induce these cells to differentiate into adult neurons and oligodendrocytes,” says W. Dalton Dietrich, scientific director of The Miami Project to Cure Paralysis. “What we want to happen is to take an embryonic stem cell and transplant it into the brain or spinal cord of an injured person. Hopefully these cells will differentiate into adult central nervous system (CNS) cells to replace the cells that die after CNS injury.”

Pantelis Tsoulfas, M.D., associate professor of neurological surgery and a member of The Miami Project team, is trying to identify molecules that signal embryonic stem cells to mature into neurons and oligodendrocytes, two of the primary cells of the central nervous system. His work re-creates, for human stem cells, conditions other researchers have used in transforming mouse stem cells into neurons.

Daniel Liebl, assistant professor of neurological surgery, is investigating the role that a family of molecules, the ephrins, may play in enabling existing stem cells in the adult brain to travel to the injured area and repair or replace the injured cells.

Jacqueline Sagen, professor of neurological surgery, is investigating factors that may guide the transformation of stem cells into the GABA cells that help control the chronic pain that plagues many individuals with spinal cord injuries. Her lab also is investigating nourishing agents that may aid in stem cell survival and differentiation.

Across the medical campus at the Diabetes Research Institute (DRI), scientists are turning to stem cells to help them overcome two major hurdles in the widespread use of islet cells—the insulin-producing cells of the pancreas—for curing diabetes. Although islet cell transplants are already reducing patients’ dependence on insulin, most must remain on immunosuppressive drugs for life, leaving them vulnerable to infections. Physicians are trying to manipulate stem cells to replace these immunosuppressive agents. They’re also optimistic stem cells will provide an unlimited supply of islet cells for transplantation.

To address the shortage of islet cells, which are isolated from donor pacreata, the DRI has opened a Pancreatic Stem Cell Development Laboratory. Juan Dominguez-Bendala, a lecturer at the DRI, and Helena Edlund, who divides her time between the University of Miami and Umea University in Sweden, are exploring various sources of insulin-producing cells, including embryonic and adult stem cells. Working with an animal model, Edlund is studying how the insulin-producing islet cells form during pancreas development. Bendala is replicating this sequence of events in the laboratory to generate new islet cells from stem cells.

So far, Bendala, who received his doctorate working with one of the teams that cloned Dolly, the sheep, in Scotland, has reported success in directing mouse stem cells to become liver cells, which are similar to those of the pancreas. He also has developed a novel protocol that is generating cells with many characteristics of islet cells and is adapting this protocol to human embryonic stem cells.

Norma Kenyon, Martin Kleiman Chair in Diabetes Research and director of the DRI’s Preclinical Islet Transplantation Program, is executive director of the new Wallace H. Coulter Center for Translational Research, established through a $13 million grant from the Wallace H. Coulter Foundation to fast-track medical breakthroughs into patented products. She is working with another set of stem cells, mesenchymal cells derived from bone marrow. There is substantial evidence these cells help patients accept foreign organs and reduce the need for immunosuppressive therapy. Mesenchymal cells also have the flexibility to become other types of mature cells. So far, Kenyon and her colleagues have found that infusions of these stem cells help prevent patients from rejecting kidney and liver transplants

Kenyon also is working with Kleiner (pediatrics, infectious disease, and immunology) to transform rat fetal stem cells into intestinal cells. The long-term goal, Kleiner says, is to replace intestinal transplants with cellular therapies. In similar work, Darwin Eton, M.D., associate professor and chief of the Division of Vascular and Endovascular Surgery, is using stem cells to re-create what happens to the body during angiogenesis—the formation of new blood vessels. By injecting stem cells that eventually develop into blood vessels, he hopes to prevent patients with insufficient blood supply to their limbs from losing limbs and suffering pain.

esenchymal cells also are the focus of Paul Schiller, Ph.D. ’87, research associate professor of endocrinology, diabetes, and metabolism, at the Miami Veterans Affairs Medical Center. Schiller has converted them into what he terms Marrow Isolated Adult Miltilineage-Inducible (MIAMI) cells. These are transformed into cells that make bone, cartilage, fat, and muscle. Ultimately, he hopes to use these cells—which are patented by the University and the Miami VA Medical Center—to restore knees damaged by osteo-arthritis and muscles damaged by traumatic accidents.

“The philosophy behind the MIAMI cell is to be able to take an individual’s own cells from his or her bone marrow, grow them in the lab to get a sufficient quantity, and then derive the desired mature tissue,” Schiller says.

Herman Cheung, a biomedical engineer who also has appointments in medicine, orthopaedics, and rehabilitation, is taking an entirely different approach to stem cell research; he is transforming mesenchymal cells into cartilage by, basically, pounding on them.

“There are many roads to Rome,” he says, showing off a large metal machine in the basement of the College of Engineering’s McArthur Annex, where mesenchymal cells embedded in tiny dots of agar, a growth medium, are being pounded to mimic the conditions experienced by the joints of a 150-pound man walking four miles an hour. Since adult stem cells serve as a repository of cells to replace those lost to injury, disease, or normal turnover, Cheung reasoned, mimicking the events that occur in nature might also create fully differentiated adult cells. It turns out he was right. The stem cells produced the growth factors needed to become chondrocytes, the cells found in human and animal cartilage.

Roland Jurecic, assistant professor of microbiology and immunology, is addressing more global questions about stem cells: How do you get these cells to reproduce in sufficient quantities to provide a pool for transplantation? Using the blood cell-forming stem cell lines of mice and humans, he is studying a gene thought to be responsible for stem cell renewal.

While no one is placing bets on when stem cells will enter the therapeutic mainstream, University of Miami physicians and scientists are confident that some day they will.

“Eventually the new procedures we’re working on will replace transplant surgery,” says Camillo Ricordi, M.D., the Stacy Joy Goodman Professor of Surgery and scientific director of the Diabetes Research Institute. “We’ll turn to regenerative medicine and cell therapy applications that just require the infusion of cells or stimulation of existing cells.”

Walking across the medical campus after having spent a half hour infusing a wide-awake patient with islet cells his surgical team brought over in a plastic cooler, he says: “When a five-hour high-risk surgery is replaced by a half-hour procedure with a 26-gauge needle, that’s remarkable progress.”